Pharmaceutical compositions of furosemide and uses thereof

ABSTRACT

A pharmaceutical composition and a method of administering the pharmaceutical composition to a patient suffering from edema, heart failure, kidney or liver disease or having symptoms thereof are disclosed. The pharmaceutical composition includes furosemide, or a pharmaceutically acceptable salt, hydrate or ester thereof and a cyclodextrin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/733,359, filed Jan. 3, 2020, which claims the benefit of and priorityto U.S. Provisional Patent Application Ser. No. 62/788,244, filed Jan.4, 2019; the contents of each of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to pharmaceutical compositions containingfurosemide and a cyclodextrin and methods of administering thepharmaceutical compositions to a patient. More specifically, the presentdisclosure relates to pharmaceutical compositions containing furosemideand a cyclodextrin and uses thereof.

BACKGROUND

Furosemide is a benzoic-sulfonamide-furan used as a potent loop diureticwith fast onset and short duration for the treatment of hypertension,edema and edema related conditions, such as congestive heart failure,cirrhosis of the liver or liver failure, and other renal diseases.Furosemide is typically administered orally for chronic treatment. Undercertain circumstances furosemide is administered parenterally topatients with decompensated heart failure or other forms of advancededema. Parenteral administration is typically done by intravenous bolusadministration of infusion.

Furosemide is poorly soluble. A typical injectable formulation isalkaline and contains 8-10 mg of furosemide per mL requiring 8-10 mL toadminister a typical clinical dose of 80 mg. Increasing theconcentration of furosemide to reduce the volume of administration maycause precipitation, impacts the stability of a pharmaceuticalformulation and presents additional challenges. Reducing the pH may alsocause precipitation.

Furthermore, certain clinical uses are precluded or restricted by a highpH in a pharmaceutical formulation, including subcutaneousadministration and use in certain infusion fluids or infusion systemswhere precipitation may occur.

Therefore, to provide a therapeutic dose of furosemide to a patient bysubcutaneous injection or small volume infusion, it is necessary for apharmaceutical composition of furosemide to have higher solubility atphysiological pH to reduce drug irritation and effective drug deliverywith minimal or negligible adverse toxicological effects.

Additionally, a furosemide formulation that is stable and suitable foradministration at neutral pH may be combined with other medications forintravenous administration. This may facilitate use of furosemide incertain circumstances such as in the critical care setting or inneonatal or pediatric use.

Thus, a need exists for therapeutically effective improvedpharmaceutical compositions containing furosemide at physiological pH.

SUMMARY

The present disclosure provides a pharmaceutical composition containingfurosemide or a pharmaceutically acceptable form of the furosemide and acyclodextrin, or cyclodextrin derivatives. The present disclosure alsoprovides a method of treating a patient suffering from edema, heartfailure, kidney or liver disease or having symptoms thereof byadministering the pharmaceutical composition containing the furosemideor any such pharmaceutical form of the furosemide and the cyclodextrinor the cyclodextrin derivatives.

In one aspect, the present disclosure provides the pharmaceuticalcomposition including the furosemide or a pharmaceutically acceptablesalt, hydrate or ester of the furosemide and the cyclodextrin. In anembodiment, the cyclodextrin is a β-cyclodextrin. The β-cyclodextrinpresent in the pharmaceutical composition is a sulfobutyl etherderivative of β-cyclodextrin. In another embodiment of the presentdisclosure, the pharmaceutical composition includes the furosemide andthe sulfobutyl ether derivative of β-cyclodextrin. In certainembodiments, the sulfobutyl ether derivative of β-cyclodextrin iscaptisol.

The present disclosure also provides the pharmaceutical compositionincluding the furosemide or derivatives thereof and a cyclodextrin orcyclodextrin derivatives for administration at a pH value from about 7.0and about 8.5. In an embodiment, the present disclosure provides thepharmaceutical composition including the furosemide or apharmaceutically acceptable salt, hydrate or ester thereof, and thecyclodextrin at an amount of less than or equal to 50% of thepharmaceutical composition. The pharmaceutical composition contains thefurosemide from about 8 mg/mL and 30 mg/mL. The pH value of thepharmaceutical composition is from about 7.0 and about 8.7. In certainembodiments, the pH value of the pharmaceutical composition is fromabout 7.2 to about 7.6.

In another aspect, the present disclosure provides a method of treatinga patient suffering from edema, heart failure, kidney or liver diseaseor having symptoms thereof. The method includes administering to thepatient a therapeutically effective amount of a pharmaceuticalcomposition containing furosemide, or a pharmaceutically acceptablesalt, hydrate or ester thereof and a cyclodextrin. In some embodiments,the method includes administering from 20 and 200 mg of the furosemide.In certain embodiments, the amount of the cyclodextrin is less than orequal to 50% of the pharmaceutical composition. In various embodiments,the method includes administering the pharmaceutical composition at a pHvalue from about 7.0 and about 8.5. In some embodiments, the methodincludes administering the pharmaceutical composition at the pH valuefrom about 7.2 and about 7.6.

In some embodiments, the present disclosure provides the pharmaceuticalcomposition for subcutaneous administration and intravenousadministration. The method further includes administering atherapeutically effective dose of the pharmaceutical composition to thepatient using a pump device. The pump device is a patch device forparenteral administration of the composition. In another embodiment, thepharmaceutical composition is administered to the patient using aninjection device. The injection device is an auto injector device. Invarious embodiments, the pharmaceutical composition is administered tothe patient subcutaneously or intravenously using the patch device orthe auto injector device.

The foregoing as well as other features and advantages of the presentdisclosure will be more fully understood from the following description,examples, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing described below is for illustration purpose only and is notintended to limit the scope of the present disclosure in any way.

FIG. 1 is a HPLC chromatographic overlay of HPLC standards, selectedfurosemide formulation stability samples, and diluent.

DETAILED DESCRIPTION

The present disclosure demonstrated in this application includes mereillustrations of the invention. A skilled artisan will appreciate thatvarious alternate embodiments and forms may be prepared. Examples,therefore, given are only for illustration purposes without anyintention to restrict the embodiments to a given set of examples.Specific functional aspects are provided merely to enable a skilledartisan to perform the invention and should not be construed aslimitations of the invention.

The use of the terms “include,” “includes,” “including,” “have,” “has,”“having,” “comprise,” “comprises,” “comprising” or the like should begenerally understood as open-ended and non-limiting unless specificallystated otherwise.

The present disclosure includes pharmaceutical compositions offurosemide and a cyclodextrin and methods of administering thepharmaceutical compositions for treating a patient suffering from edema,heart failure, kidney or liver disease or having such disease symptoms.More specifically, the present disclosure provides the pharmaceuticalcompositions having the furosemide and a β-cyclodextrin or a derivativeof β-cyclodextrin such as a sulfobutyl ether derivative. In certainembodiments, the sulfobutyl ether derivative of β-cyclodextrin iscaptisol. The cyclodextrin can be at an amount of less than or equal to50% of the pharmaceutical composition at a pH value from about 7.0 toabout 8.7. The pharmaceutical composition is suitable for parenteraladministration, more specifically, suitable for subcutaneous andintravenous administration. The pharmaceutical compositions are usefulin the treatment of edema, hypertension or heart failure in a patienthaving or exhibiting symptoms of such conditions.

As used herein, “furosemide” refers to a compound having the formulaC₁₂H₁₀ClN₂O₅S or C₁₂H₁₁ClN₂O₅S and pharmaceutically acceptable salts,hydrates and esters thereof, for example, furosemide sodium salt(C₁₂H₁₀ClN₂NaO₅S) and furosemide quaternary ammonium salts or any of theamino acid salts including basic amino acids of natural origin such asornithine, lysine and arginine, which shall include L-arginine,DL-arginine, L-lysine, DL-lysine, L-ornithine, DL-ornithine, orhistidine and any variations thereof. Furosemide can be referred to byother names, such as frusemide,5-(aminosuiphonyl)-4-chloro-2-[(2-furanyi-methyl) amino] benzoic acid,or its IUPAC name, 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoicacid, or its common trade names, such as Lasix, Furosemid andFuranthril. It is understood that “furosemide” will further refer to anyprecursor or metabolite, such as4-chloro-N-furyl-5-sulfamoyl-anthranylic acid as may be required foradministration.

As used herein, “cyclodextrin” refers to cyclic compounds of 5 or moreα-D-glucopyranoside units linked by 1,4 glycosidic bonds, or compoundscontaining glucose monomers ranging from six to eight units in a ringdesignated as 6 glucose subunits known as α-cyclodextrin, 7 glucosesubunits known as β-cyclodextrin and with 8 glucose subunits known asγ-cyclodextrin. In addition, the present disclosure includescyclodextrin-related compounds, for example, compounds derived fromcyclodextrins or structurally-related to cyclodextrins.

As used herein, “CAPTISOL®” refers to the trade name for a proprietarymodified mixture of cyclodextrin preparation with a modified structureto optimize the solubility and stability of drugs. CAPTISOL® is amixture of polyanionic β-cyclodextrin derivatives of a sodium sulfonatesalt tethered to the lipophilic cavity of a butyl ether group, orsulfobutyl ether. CAPTISOL® is commercially available from LigandPharmaceuticals Inc. located in San Diego, Calif.

As used herein, the term “captisol” is a mixture of polyanionicβ-cyclodextrin derivatives of a sodium sulfonate salt separated from thehydrophobic cavity of the β-cyclodextrin with a butyl ether spacergroup. Chemically, captisol is also referred to as sulfobutyl etherbeta-cyclodextrin sodium.

As used herein, “derivative” refers to a modified form of a compoundgenerated by various methods or processes including, but not limited to,methylation, acetylation, substitutions such as alkylation, amidation,quaternization, thiolation, sulfation, and oxidation, chain elongationssuch as cross-linking and grafting, and depolymerization by chemical,physical, or biological including enzymatic means. The methods andprocesses can be employed either alone or in any combination without anyspecific order.

As used herein, “preventing or treating” refers to partially orcompletely alleviating and/or ameliorating the condition and/or symptomsthereof, and/or preventing its re-occurrence or halting its progression.The present disclosure accordingly includes a method of providing to thepatient a combination product that includes a compound or therapeuticcomposition of the present disclosure in combination or association witha pharmaceutically acceptable carrier, solubilizer or an appropriatebuffer.

As used herein, “pharmaceutically acceptable” refers to a substance thatis acceptable for use in pharmaceutical applications from atoxicological perspective and does not adversely interact with theactive ingredient. Accordingly, pharmaceutically acceptable carriers arethose that are compatible with the other ingredients in the formulationand are biologically acceptable. Supplementary active ingredients canalso be incorporated into the pharmaceutical compositions.

As used herein, “therapeutically effective” refers to a substance or anamount that elicits a desirable biological activity or effect reducingor arresting disease processes. For example, a “therapeuticallyeffective amount” of a composition can deliver a dose (also referred toas a “therapeutic dose”) sufficient to elicit the desired biologicalresponse. In the present invention, the desired biological response is“treating” of edema, heart failure, kidney or liver disease or havingsymptoms thereof. As used herein, “treating” refers to partially orcompletely alleviating and/or ameliorating the condition and/or symptomsthereof.

As used herein, “administration” refers to parenteral includingintravenous, subcutaneous, topical, transdermal, intradermal,transmucosal, intraperitoneal, intramuscular, intracapsular,intraorbital, intracardiac, transtracheal, subcuticular, intraarticular,subcapsular, subarachnoid, intraspinal, epidural and intrasternalinjection and infusion, unless specifically mentioned. Specifically, thepharmaceutical composition of the present disclosure can be administeredparenterally including infusion, injection or implantation, whichincludes subcutaneous and intravenous administration. When administeredfor the treatment of a disease state or disorder, it is understood thatan effective dosage can vary depending upon many factors such as thecompound or therapeutic composition utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound or therapeutic composition of thepresent disclosure can be provided to a patient already suffering from adisease, for example, edema related disorders, in an amount sufficientto at least partially ameliorate the symptoms of the disease and itscomplications and halt or slow down the disease progression. Ifadministered to a patient suffering from the condition prior to clinicalmanifestation, the administration of a therapeutic composition mayprevent the first clinical manifestation or delay its onset.

As used herein, “patient” refers to a mammal, such as a human or adomesticated animal such as a pet or livestock.

As used herein, the term “about” refers to a ±10% variation from thenominal value unless otherwise indicated or inferred. For example, incertain applications, such as pH measurements, the term “about” canrefer to a ±5%, or a ±2.5%, or a ±1% variation from the nominal value ora fixed variation from the nominal value, for example, ±0.1 pH units or±0.2 pH units.

The present disclosure provides the pharmaceutical compositions thatinclude the furosemide or a therapeutic combination includingfurosemide, and one or more pharmaceutically acceptable carriers,excipients, or diluents such as a buffer. The excipients may includesodium chloride, sodium hydroxide, water, glycerol, mannitol, sodiumphosphate, sodium carbonate, lactose, dextrose and other electrolytes.

Examples of such carriers are well known to skilled artisan and can beprepared in accordance with acceptable pharmaceutical procedures suchas, for example, those described in Remington: The Science and Practiceof Pharmacy, 20th edition, ed. Alfonso R. Gennaro (Lippincott Williams &Wilkins, Baltimore, Md. (2000)). For example, liquid media or liquidcarriers (which are used interchangeably herein) can be used inpreparing the pharmaceutical compositions of the present disclosure suchas solutions, suspensions, and emulsions. A compound described hereincan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as a buffer, an organic solvent, and/or pharmaceuticallyacceptable oils and/or fats.

The pharmaceutical compositions of the present disclosure can includeother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, suspending agents, thickeningagents, colors, viscosity regulators, stabilizers, adsorbents, binders,antioxidants, bulking agents, pH adjusting agents, preservative,solvent, fluidizing agents and osmo-regulators. As the presentdisclosure provides the pharmaceutical compositions and their intendeduse is with the patients, each of the ingredients or compounds of thepharmaceutical compositions described herein can be a pharmaceuticallyacceptable ingredient or compound.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise.

It is understood that the order of steps or order for performing certainactions can be changed so long as the intended result is obtained.Moreover, two or more steps or actions may be conducted simultaneously.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps

Pharmaceutical Compositions Containing Furosemide and Methods ofTreatment

The present disclosure provides the pharmaceutical composition andmethods of treatment with the pharmaceutical composition containing thefurosemide and the cyclodextrin or cyclodextrin derivatives foradministration to a patient with strikingly higher aqueous solubility atlower pH with enhanced drug stability, reduced drug irritation, andreduced drug incompatibility when used with other infusion formulations.

Cyclodextrins

Cyclodextrins are cyclic carbohydrates that differ from one another bythe number of gluco-pyranose units in the structure. The cyclodextrinstructure provides a molecule shape like a truncated cone with ahydrophilic exterior surface and hydrophobic interior cavity. Theseproperties make cyclodextrins very valuable for drug administration. Thehydrophilic surface provides cyclodextrins with good water solubilityand the hydrophobic cavity creates a suitable position to include a drugmolecule. A variety of non-covalent forces, such as van der Waalsforces, hydrophobic interactions and other forces are responsible forthe formation of stable complexes of cyclodextrins and drug molecule.Many processes are used to form cyclodextrin-drug complexes, such asco-precipitation, heating, extrusion, dry mixing, damp mixing, slurrycomplexation, and paste complexation. Oral uses of the naturallyoccurring cyclodextrins is well-known with limited parenteral use andapplications. Therefore, modified forms of cyclodextrins are generallyused in parenteral and other routes of administration for higherstability and bioavailability.

One such modified cyclodextrin is captisol, which is an anionicβ-cyclodextrin derivative with sodium sulfate salt separated from thehydrophobic cavity with a butyl ether spacer group. Parenteral studieswith captisol demonstrate a substantially higher safety profile withsubstantially higher complexation characteristics and water stabilitygreater than 35 times over the parent cyclodextrin.

Exemplary cylcodextrins for use in the present pharmaceuticalcompositions include, for example, a beta-cyclodextrin, agamma-cyclodextrin, a sulfobutyl-ether-beta-cyclodextrin, ahydroxy-propyl-beta-cyclodextrin, and a randomly methylatedbeta-cyclodextrin.

Pharmaceutical Compositions Containing Furosemide

The present disclosure relates to the pharmaceutical composition of thefurosemide and the cyclodextrin or derivatives thereof, such asβ-cyclodextrin derivative (e.g., captisol). The route of administrationfor the pharmaceutical composition can be parenteral, more specifically,subcutaneous and intravenous route. The specific amount of thecyclodextrin is less than or equal to about 50% of the pharmaceuticalcomposition and the pH values achieved from about 7.0 to about 8.5. Assuch, one advantage of the disclosure is that furosemide can beadministered by subcutaneous infusion or injection to the patient inneed thereof. Another advantage of the present disclosure is the abilityto administer a therapeutic dose of the furosemide such as 80 mg withinthe standardized volume of a common cartridge used in drug delivery,i.e., 3-5 mL, to the patient using an infusion device, such as a patchpump. Yet another advantage of the present disclosure is the ability toadminister a therapeutic dose of the furosemide, such as 50 mg, by meansof an injection device such as an autoinjector. Yet another advantage ofthe present disclosure is the use in intravenous infusion when otherinfusion fluids are used concurrently or sequentially without the needfor line flushing before and after administration of furosemide. Yetanother advantage of the present disclosure is that the pharmaceuticalcomposition remains stable at the pH value from about 7.0 to about 8.3and is compatible for subcutaneous or intravenous administration of thefurosemide with effective delivery and minimal or negligible adversetoxicological effects.

In one embodiment of the present disclosure, the pharmaceuticalcomposition remains stable at the pH value of from about 7.0 to about8.5. In certain embodiments of the present disclosure, thepharmaceutical composition remains stable at the pH value from 7.2 to7.6 for subcutaneous or intravenous administration of furosemide.

The furosemide can be present in the pharmaceutical composition asfurosemide or in the form of any variations of analogs such as apharmaceutically acceptable salt, hydrate or an ester. In certainembodiments, the amount of the furosemide in the pharmaceuticalcomposition is from about 8 mg/mL to about 40 mg/mL. In someembodiments, the amount of the furosemide is from about 15 mg/mL toabout 26 mg/mL. The pharmaceutical composition further contains thecyclodextrin or derivatives thereof at an amount of less than or equalto 50% and maintain the pH value of the pharmaceutical composition fromabout 7.0 to about 8.5. In certain embodiments, the pH value of thepharmaceutical composition is maintained from about 7.2 to about 7.6.

In certain embodiments, the amount of the furosemide in thepharmaceutical composition is from about 8 mg/mL to about 40 mg/mL andthe cyclodextrin is included in the pharmaceutical composition at anamount less than or equal to 50%. The pH value of the pharmaceuticalcomposition is maintained from about 7.2 to about 7.6. One advantage ofthe combination of the ingredients in the disclosed amounts and at thedisclosed conditions is that therapeutic dose of the furosemide such as80 mg can be accommodated within a standard size cartridge of the patchpump, e.g., 3-5 mL, and administered to the patient, orself-administered by the patient using, for example, the patch pump.

In some embodiments, the amount of the furosemide in the pharmaceuticalcomposition is from about 8 mg/mL to about 40 mg/mL. In certainembodiments, the amount of the sulfobutyl ether derivative ofβ-cyclodextrin (e.g., captisol), in the pharmaceutical composition isless than or equal to 50%. In certain embodiments, the pH value of thepharmaceutical composition is from about 7.0 to about 8.5. In yetanother embodiment, the above pharmaceutical composition is administeredto the patient subcutaneously or intravenously as needed.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition, comprising:

from about 40 mM to about 160 mM of a diuretic selected from the groupconsisting of 4-chloro-2-((furan-2-ylmethyl)amino)-5-sulfamoylbenzoicacid, a pharmaceutically acceptable salt thereof, and a mixture of theforegoing;

from about 45 mM to about 190 mM of a sulfobutyl ether derivative ofβ-cyclodextrin; and

water; wherein the pharmaceutical composition has a pH value from about7.0 to about 8.5.

The pharmaceutical composition can be further characterized according tothe amount of sulfobutyl ether derivative of β-cyclodextrin. Forexample, in certain embodiments, the pharmaceutical compositioncomprises from about 120 mM to about 160 mM of a sulfobutyl etherderivative of β-cyclodextrin. In certain embodiments, the pharmaceuticalcomposition comprises from about 135 mM to about 145 mM of a sulfobutylether derivative of β-cyclodextrin. In certain embodiments, thesulfobutyl ether derivative of β-cyclodextrin is sulfobutyl etherbeta-cyclodextrin sodium.

The pharmaceutical composition can be further characterized according tothe amount of diuretic. For example, in certain embodiments, thepharmaceutical composition comprises from about 80 mM to about 100 mM ofthe diuretic. In certain embodiments, the pharmaceutical compositioncomprises about 91 mM of the diuretic.

In certain embodiments, the pharmaceutical composition further comprisesa buffer. In certain embodiments, the buffer comprisestris(hydroxymethyl)aminomethane. In certain embodiments, the buffer ispresent in an amount ranging from about 1 mM to about 50 mM. In certainembodiments, the buffer is present in an amount of about 25 mM.

In certain embodiments, the pharmaceutical composition has a pH of fromabout 7.0 to about 8.0. In certain embodiments, the pharmaceuticalcomposition has a pH of about 7.4.

In certain embodiments, the pharmaceutical composition contains at least50% (w/w) water.

The pharmaceutical composition of the present disclosure contains thefurosemide with high solubility and enhanced stability, whichadvantageously enables administration of a higher dose of the furosemidein lower volume of the pharmaceutical composition. The pharmaceuticalcomposition of the present disclosure achieves the administration of thehigher concentration of the furosemide at a pH value that is compatiblefor subcutaneous administration to the patient. More specifically, thepharmaceutical composition is stable and suitable for subcutaneous orintravenous administration.

In some embodiments, the present disclosure includes the pharmaceuticalcomposition of the furosemide at a higher concentration in a drug volumeof 2-20 mL. In another embodiment, the amount of the cyclodextrin in thepharmaceutical composition is less than or equal to 50%. In yet anotherembodiment, the pharmaceutical composition has the pH value from about7.0 to about 8.5 compatible for subcutaneous and intravenousadministration.

In some embodiments, the present disclosure includes the pharmaceuticalcomposition of the furosemide and the cyclodextrin or cyclodextrinderivative, such as captisol, at an amount from about 40% to about 50%.

Methods of Treatment

In another embodiment, the present disclosure includes a method oftreating the patient with or exhibiting symptoms of edema, heartfailure, kidney or liver disease by administering to the patient thepharmaceutical composition containing furosemide, or thepharmaceutically acceptable salt, hydrate or ester thereof. Moreparticularly, the pharmaceutical composition contains furosemide, or thepharmaceutically acceptable salt, hydrate or ester thereof at an amountof about 30 mg/mL. The pharmaceutical composition further contains thecyclodextrin at an amount of less than or equal to 50% in thepharmaceutical composition.

In one embodiment, the pharmaceutical composition is administered to thepatient subcutaneously. Specifically, the pharmaceutical composition isadministered to the patient subcutaneously using a pump device or aninjection device. The pump device can include, for example, a patchdevice. The injection device can include, for example, an auto injectordevice. In another embodiment, the pharmaceutical composition isadministered to the patient intravenously. Specifically, thepharmaceutical composition is administered to the patient intravenouslyusing the pump device or the injection device. In various embodiments,the pharmaceutical composition is administered to the patientsubcutaneously or intravenously using the patch device or the autoinjector device. In some embodiments, the present disclosure includesthe method of treating the patient with or exhibiting symptoms of edema,heart failure, kidney or liver disease by administering to the patientthe pharmaceutical composition of furosemide, or the pharmaceuticallyacceptable salt, hydrate or furosemide ester with an amount of thefurosemide in the pharmaceutical composition to about 40 mg/mL. Thepharmaceutical composition further contains the cyclodextrin orderivatives thereof at an amount of less than or equal to 50% at the pHvalue of the pharmaceutical composition from about 7.2 and about 7.6. Inone embodiment, the cyclodextrin is a β-cyclodextrin. In anotherembodiment the cyclodextrin is a sulfobutyl ether derivative ofβ-cyclodextrin. In yet another embodiment, the sulfobutyl etherderivative of β-cyclodextrin is captisol. In one embodiment, the pHvalue of the pharmaceutical composition is from about 7.0 to about 7.8.In certain embodiments, the pH value is maintained from about 7.0 toabout 8.3.

In an embodiment, the patient suffering from edema, heart failure,kidney or liver disease or exhibiting such symptoms thereof isadministered with the pharmaceutical composition with the amount of thefurosemide from about 8 mg/mL to about 40 mg/mL. In another embodiment,the amount of the captisol in the pharmaceutical composition is lessthan or equal to 50%. In another embodiment, the pH of thepharmaceutical composition is from about 7.0 to about 8.5.

In another embodiment, the present disclosure provides a method oftreating a patient suffering from a condition selected from edema, heartfailure, kidney disease, or liver disease, or having a symptom any ofthe foregoing, comprising administering to the patient in need thereof atherapeutically effective amount of a pharmaceutical composition ofdescribed herein treat the condition. In certain embodiments, thecondition is edema. In certain embodiments, the condition is heartfailure. In certain embodiments, the condition is kidney disease orliver disease.

In some embodiments, the pharmaceutical composition is administered tothe patient parenterally including subcutaneous or intravenousadministration. In the present disclosure, several devices can be usedto facilitate self-administration of the pharmaceutical composition. Thedevice typically includes a reservoir or a cartridge, for example,pre-loaded with the pharmaceutical composition to be administered, orinserted into the device prior to its use. For example, a micropump canprovide precise parenteral administration of desired quantities of aliquid pharmaceutical composition. Another type of device useful forparenteral delivery or administration of pharmaceutical composition isoften referred to as the pump device or the injection device.

In some embodiments, the present disclosure includes medical devices ofa unitary construction. Such medical devices can be for a single use. Incertain embodiments, the medical device can be of a multi-piececonstruction. In such medical devices, a disposable or a reusableportion or component can be present. For example, a housing defining orincluding the reservoir can be a disposable or a reusable component ofthe medical device.

The patch pump or patch device of the present disclosure may include apump device having a drug reservoir and electrolytically, manually,mechanically, automatically or electronically driven piston. The drugpump device may be furnished with a prefilled cartridge. If a glasscartridge or cartridge of other suitable pharmaceutical-grade compositematerial is used, the drugs can be stored in the pump device forlong-term shelf life or inserted into the device just prior to use. Thedrug pump device may be implantable, include an adhesive patch foradhesion to patient's skin, or maybe worn on a belt or is attached tothe body by a strap or by other means.

Additional Features of Pharmaceutical Compositions and Methods ofTreatment

The pharmaceutical forms of the present disclosure suitable forinjection can include sterile aqueous solutions or dispersions for theextemporaneous preparation of sterile injectable solutions ordispersions. In certain embodiments, the pharmaceutical form is sterile,and its viscosity permits it to flow through an infusion line or needle.The pharmaceutical form should be stable under the conditions ofmanufacture and storage, for example, preserved against thecontaminating action of microorganisms, if needed. The carrier can be asolvent or dispersion medium containing liquids such as water, ethanol,polyol (for example, glycerol, propylene glycol, and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oils.

In the present disclosure, the pharmaceutical compositions can achievehigher level of the furosemide suitable for administration. For example,the amount of the furosemide in the pharmaceutical composition can beabout 8 mg/mL or greater, about 10 mg/mL or greater, or about 15 mg/mLor greater. In various embodiments, the amount of the furosemide can beabout 15 mg/mL or greater, about 20 mg/mL or greater, about 26 mg/mL orgreater, or about 30 mg/mL, or about 40 mg/mL.

Concentration of Furosemide

In some embodiments, the furosemide can be present in an amount fromabout 8 mg/mL to about 40 mg/mL, about 10 mg/mL to about 26 mg/mL, fromabout 10 mg/mL to about 30 mg/mL, from about 10 mg/mL to about 15 mg/mL,from about 15 mg/mL to about 40 mg/mL, from about 16 mg/mL to about 24mg/mL, from about 20 mg/mL to about 40 mg/mL.

Disorders for Treatment

In the present disclosure, furosemide, therapeutic combinations, andpharmaceutical compositions can be useful for treating a pathologicalcondition or disorder or symptoms in the patient. The present disclosureprovides administering higher concentrations of the furosemideparenterally to alleviate the disorders, such as edema, heart failure,kidney or liver disease or having such symptoms. The present disclosureaccordingly includes the method of providing to the patient thepharmaceutical composition that includes a compound or therapeuticcombination of the present disclosure in combination or association witha pharmaceutically acceptable carrier or solubilizer or a suitablebuffer. Compounds and therapeutic combinations of the present disclosurecan be administered alone or in combination with other therapeuticallyeffective compounds or therapies for the treatment of a pathologicalcondition or disorder.

The present disclosure also includes the methods of administration ofthe pharmaceutical composition including the furosemide or one or moreof its analogues or variations or precursors to the patient with edemarelated disease or disorder. The edema related disease or disorder mayalso include heart failure, chronic kidney disease.

pH of Pharmaceutical Composition

In certain embodiments, the pharmaceutical composition can have the pHvalue in the range of about 7.0 to about 8.7. In certain embodiments,the pharmaceutical formulations can have the pH value in the range ofabout 7.0 to about 8.5, or about 7.2 to about 7.6 or about 7.3 to about7.8. In some embodiments, the pharmaceutical composition can have the pHvalue in the range of about 7.4 to about 8.0, or about 7.4 to about 9.0.

Amount of Cyclodextrin

Further, in various embodiments, the cyclodextrin in the pharmaceuticalcomposition can be less than or equal to about 50%. In some embodiments,the cyclodextrin in the pharmaceutical composition can be less than orequal to about 50%. In some embodiments, the amount of the cyclodextrincan be less than or equal to about 35%, less than or equal to about 30%,or less than or equal to about 25%. In certain embodiments, the amountof the cyclodextrin can be in a range of about 5% to about 50%, about40% to about 50%, about 20% to about 40%, or about 20% to about 30%. Incertain embodiments, the amount of the cyclodextrin can be about 10% orabout 40%.

Further, in certain embodiments, the cyclodextrin in the pharmaceuticalcomposition can be less than or equal to about 45% (w/w). In someembodiments, the cyclodextrin in the pharmaceutical composition can beless than or equal to about 40% (w/w). In some embodiments, the amountof the cyclodextrin can be less than or equal to about 35%, less than orequal to about 20% (w/w), or less than or equal to about 15% (w/w). Incertain embodiments, the amount of the cyclodextrin can be in a range ofabout 10% (w/w) to about 50% (w/w), about 35% (w/w) to about 50% (w/w),about 25% (w/w) to about 40% (w/w), or about 25% (w/w) to about 30%(w/w). In certain embodiments, the amount of the cyclodextrin can be ina range of about 20% (w/w) to about 30% (w/w). In certain embodiments,the amount of the cyclodextrin can be about 15% (w/w) or about 45%(w/w).

The amount of cyclodextrin in the pharmaceutical composition may becharacterized according to the molar ratio of cyclodextrin to furosemidein the pharmaceutical composition. For example, in certain embodiments,the molar ratio of cyclodextrin (e.g., captisol) to furosemide isgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.In certain embodiments, the molar ratio of cyclodextrin to furosemide isgreater than about 2. In certain embodiments, the molar ratio ofcyclodextrin to furosemide is greater than about 3. In certain otherembodiments, the molar ratio of cyclodextrin to furosemide is from 2:1to about 15:1. In certain other embodiments, the molar ratio ofcyclodextrin to furosemide is from 2:1 to about 3:1. In certain otherembodiments, the molar ratio of cyclodextrin to furosemide is from 2:1to about 5:1. In certain other embodiments, the molar ratio ofcyclodextrin to furosemide is from 5:1 to about 10:1

Therapeutic Benefits

In the present disclosure, the pharmaceutical composition may reduce thedisease condition and symptoms by at least about 5% to at least about99% as compared to an untreated patient. The compound may beadministered to the patients in various forms including, an injection, atransdermal patch, and sustained-release formulations. The compositionmay be administered via enteral or parenteral route including,intravenous, subcutaneous, topical, transdermal, intradermal,transmucosal, intraperitoneal, intramuscular, intracapsular,intraorbital, intracardiac, transtracheal, subcuticular, intraarticular,subcapsular, subarachnoid, intraspinal, epidural and intrasternalinjection and infusion.

The typical dosages of the compounds and the compositions of the presentdisclosure may vary within a wide range depending on many factors,including but not limited to, route of administration, treatment stage,pretreatment use of oral medications, body weight, age and generalcondition of the patient.

Amount of Water in the Pharmaceutical Composition

The pharmaceutical composition may be further characterized according tothe amount of water in the pharmaceutical composition. In certainembodiments, pharmaceutical composition comprises at least 40% (w/w),45% (w/w), 50% (w/w), 55% (w/w), 60% (w/w), 65% (w/w), 70% (w/w), 75%(w/w), 80% (w/w), or 85% (w/w) water. In certain embodiments,pharmaceutical composition comprises at least 90% (w/w), 91% (w/w), 92%(w/w), 93% (w/w), 94% (w/w), 95% (w/w), 96% (w/w), 97% (w/w), 98% (w/w),or 99% (w/w) water. In certain embodiments, pharmaceutical compositioncomprises at least 50% (w/w). In certain embodiments, pharmaceuticalcomposition comprises at least 55% (w/w). In certain embodiments,pharmaceutical composition comprises at least 60% (w/w). In certainembodiments, pharmaceutical composition comprises at least 65% (w/w). Incertain embodiments, pharmaceutical composition comprises at least 95%(w/w) water. In certain embodiments, pharmaceutical compositioncomprises at least 96% (w/w) water. In certain embodiments,pharmaceutical composition comprises at least 97% (w/w) water. Incertain embodiments, pharmaceutical composition comprises at least 98%(w/w) water. In certain embodiments, pharmaceutical compositioncomprises at least 99% (w/w) water. In certain embodiments, thepharmaceutical composition comprises from about 50% (w/w) to about 70%(w/w) water. In certain embodiments, the pharmaceutical compositioncomprises from about 60% (w/w) to about 70% (w/w) water.

Buffer

In certain embodiments, the pharmaceutical composition comprises abuffer. In certain embodiments, buffer is present in the pharmaceuticalcomposition in an amount less than about 1% (w/w), 2% (w/w), 3% (w/w),4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), or 10%(w/w). In certain embodiments, the buffer may comprise phosphoric acid,citric acid, acetic acid, histidine, lactic acid, tromethamine, gluconicacid, aspartic acid, glutamic acid, tartaric acid, succinic acid, malicacid, fumaric acid, or alpha-ketoglutaric acid.

Additional Components of the Pharmaceutical Composition

The pharmaceutical composition of the present disclosure may alsocontain adjuvants, diluents, excipients and/or carriers, known in theart, compatible with the compounds and the other ingredients of thepharmaceutical composition, and not deleterious to the recipientthereof.

Stability of the Pharmaceutical Compositions

The pharmaceutical composition may be further characterized according tostability of the pharmaceutical composition to storage. This can beachieved by storing a pharmaceutical composition at a designatedtemperature for a duration of time, then removing an aliquot of thepharmaceutical composition, and analyzing the aliquot to determine ifany components in the original pharmaceutical composition have degraded.For example, the aliquot can be subjected to visual analysis todetermine the presence of any undissolved solids and/or a change incolor or clarity of the solution. Also, the aliquot can be analyzed todetermine the amount of diuretic present (e.g., furosemide or apharmaceutically acceptable salt thereof) relative to the originalamount of diuretic in the pharmaceutical composition.

Accordingly, in certain embodiments, less than 4% of the diureticdegrades upon storage of the pharmaceutical composition at 40° C. for 29days. In certain embodiments, less than 1% of the diuretic degrades uponstorage of the pharmaceutical composition at 40° C. for 29 days. Incertain embodiments, less than 0.5% of the diuretic degrades uponstorage of the pharmaceutical composition at 40° C. for 29 days. Incertain embodiments, less than 0.1% of the diuretic degrades uponstorage of the pharmaceutical composition at 40° C. for 29 days. Incertain embodiments, less than 10% of the diuretic degrades upon storageof the pharmaceutical composition at 70° C. for 29 days. In certainembodiments, less than 7% of the diuretic degrades upon storage of thepharmaceutical composition at 70° C. for 29 days. In certainembodiments, less than 5% of the diuretic degrades upon storage of thepharmaceutical composition at 70° C. for 29 days. In certainembodiments, less than 3% of the diuretic degrades upon storage of thepharmaceutical composition at 70° C. for 29 days. In certainembodiments, less than 1% of the diuretic degrades upon storage of thepharmaceutical composition at 70° C. for 29 days. In certainembodiments, less than 3% of the diuretic degrades upon storage of thepharmaceutical composition at 25° C. for 24 months. In certainembodiments, less than 2% of the diuretic degrades upon storage of thepharmaceutical composition at 25° C. for 24 months. In certainembodiments, less than 1% of the diuretic degrades upon storage of thepharmaceutical composition at 25° C. for 24 months. In certainembodiments, less than 0.5% of the diuretic degrades upon storage of thepharmaceutical composition at 25° C. for 24 months. In certainembodiments, less than 0.1% of the diuretic degrades upon storage of thepharmaceutical composition at 25° C. for 24 months. In certainembodiments, less than 0.05% of the diuretic degrades upon storage ofthe pharmaceutical composition at 25° C. for 24 months.

Additionally, in certain embodiments, the pharmaceutical composition ischaracterized by the purity of the diuretic in the pharmaceuticalcomposition upon storage. For example, in certain embodiments, the afterstorage of the pharmaceutical composition at 40° C. for 29 days thediuretic has a purity of at least 97%. In certain embodiments, afterstorage of the pharmaceutical composition at 40° C. for 29 days thediuretic has a purity of at least 98%. In certain embodiments, afterstorage of the pharmaceutical composition at 40° C. for 29 days thediuretic has a purity of at least 99%. In certain embodiments, afterstorage of the pharmaceutical composition at 40° C. for 29 days thediuretic has a purity of at least 99.5%. In certain embodiments, afterstorage of the pharmaceutical composition at 40° C. for 29 days thediuretic has a purity of at least 99.9%. In certain embodiments, theafter storage of the pharmaceutical composition at 70° C. for 29 daysthe diuretic has a purity of at least 95%. In certain embodiments, afterstorage of the pharmaceutical composition at 70° C. for 29 days thediuretic has a purity of at least 97%. In certain embodiments, afterstorage of the pharmaceutical composition at 70° C. for 29 days thediuretic has a purity of at least 98%. In certain embodiments, afterstorage of the pharmaceutical composition at 70° C. for 29 days thediuretic has a purity of at least 99%. In certain embodiments, afterstorage of the pharmaceutical composition at 70° C. for 29 days thediuretic has a purity of at least 99.5%. In certain embodiments, theafter storage of the pharmaceutical composition at 25° C. for 24 monthsthe diuretic has a purity of at least 97%. In certain embodiments, afterstorage of the pharmaceutical composition at 25° C. for 24 months thediuretic has a purity of at least 98%. In certain embodiments, afterstorage of the pharmaceutical composition at 25° C. for 24 months thediuretic has a purity of at least 99%. In certain embodiments, afterstorage of the pharmaceutical composition at 25° C. for 24 months thediuretic has a purity of at least 99.5%. In certain embodiments, afterstorage of the pharmaceutical composition at 25° C. for 24 months thediuretic has a purity of at least 99.9%.

Exemplary Benefits of the Pharmaceutical Compositions

Various embodiments of the present disclosure enable administration ofhigher concentrations of the furosemide to the patient. Further, thepharmaceutical composition of various embodiments of the presentdisclosure has the pH appropriate for subcutaneous or intravenousadministration of the composition to the patient.

Another advantage of the embodiments of the present disclosure is thatthe pharmaceutical compositions with higher concentration of thefurosemide and lower amount of the captisol can be administered with thepump device or the injection device.

Yet another advantage of the pharmaceutical compositions of the presentdisclosure is substantially high solubility at a desired pH, which mayfacilitate intravenous infusion by allowing co-administration with otherinfusion fluids or pharmaceutical formulations.

It has been observed that the furosemide demonstrates higher solubilityand enhanced stability in pharmaceutical compositions in combinationwith the cyclodextrins or cyclodextrin derivatives such as sulfobutylether derivative of β-cyclodextrin compared to other excipients with thefurosemide for treatment of edema, hypertension and other renaldiseases.

Unit Container

Another aspect of the disclosure provides a unit container comprising apharmaceutical composition described herein. In certain embodiments, thecontainer contains from about 1 mL to about 10 mL, from about 1 mL toabout 5 mL, from about 1 mL to about 4 mL, from about 1 mL to about 3mL, from about 1 mL to about 2 mL, from about 1 mL to about 1.5 mL, fromabout 2 mL to about 5 mL, or from about 2 mL to about 3 mL ofpharmaceutical composition. In certain embodiments, the containercontains from about 1 mL to about 3 mL of pharmaceutical composition. Incertain embodiments, the container contains from about 2 mL to about 3mL of pharmaceutical composition. In certain embodiments, the containercontains from about 5 mL to about 10 mL of pharmaceutical composition.In certain embodiments, the container contains from about 8 mL to about10 mL of pharmaceutical composition.

Medical Kits

Another aspect of the invention provides a medical kit comprising, forexample, (i) a pharmaceutical composition described herein, and (ii)instructions for use, such as for use in a method described herein.

It is understood that the examples, embodiments and teachings presentedin this application are described merely for illustrative purposes. Anyvariations or modifications thereof are to be included within the scopeof the present application as discussed.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1— Preparation of Exemplary Aqueous Furosemide Formulation

An exemplary aqueous furosemide formulation was prepared according tothe procedure set forth below. The aqueous furosemide formulationcontained furosemide at a concentration of 30 mg/mL, captisol at aconcentration of about 300 mg/mL, and tris(hydroxymethyl)aminomethanebuffer at a concentration of 25 mM. The formulation had a pH of 7.4.

Captisol (157.65 g, 5.1% water, USP grade, Hovione) was slowly addedover about 6.5 minutes (to facilitate dissolution and avoid clumping),while stirring with a magnetic stir bar, to approximately 350 mL ofwater for injection (Rocky Mountain Biologics, Product No. WIFI-USP-1X6)in a 1-L beaker. Tris(hydroxymethyl) aminomethane free-base (1.514 g,Sigma, Product No. 101974108) was added over about 3 minutes, then 3.6mL of 10 N NaOH solution (Fisher, Product No. S71993-1) was added overabout 2.5 minutes. Furosemide (15.0 g, USP grade, Spectrum, Product No.F1133) was added slowly and dissolved over about one hour, with additionof about 5 μL 10 N NaOH (to maintain pH in the range of 7.4-7.5), andsonication (at 26-28 minutes, 31-36 minutes, 38-43 minutes, and 50-55minutes during the one hour dissolution period). The solution was pouredfrom the beaker into a 500-mL volumetric flask. The beaker was rinsedwith approximately 20 mL of water for injection, which was then added tothe volumetric flask. The solution was diluted to nearly 500 mL withwater for injection, and the pH was determined to ensure that it was inthe range of 7.4-7.5. The solution was diluted to 500 mL with water forinjection, and the pH was determined to be 7.408. Finally, the solutionwas filtered through an Argos Bottle-Top Filter System (Product No.BPV2250) in a laminar flow hood.

Example 2— Stability Analysis of Exemplary Furosemide Formulation

A stability analysis was conducted on exemplary furosemide formulationsprepared using procedures similar to that described in Example 1.Experimental procedures and results are provided below.

Part I—Experimental Procedures

Aqueous furosemide formulations A-H described in Table 1, below, wereprepared according to the following general procedure. The requiredamounts of captisol (50, 100, or 150 grams) andtris(hydroxymethyl)aminomethane free-base (1.5 g, in formulations whereit was included) were added to a 500-mL volumetric flask. Water forinjection (about 350 mL) was added, and the solids were dissolved byshaking and/or swirling the flask. Sodium hydroxide (10 N) was added inan amount sufficient to deprotonate the carboxylic acid group offurosemide (3.6 mL for formulations with, and 4.5 mL for formulationswithout, tris(hydroxymethyl) aminomethane free-base). Furosemide (15 g)was added, and the mixture was mixed by swirling, shaking, and/orsonication for about 10 minutes. Sodium hydroxide (1 N or 10 N) wasadded dropwise to adjust the pH to the desired value (7.4 or 8.4). Thesolution was diluted to 500 mL with water for injection, then filteredinto vials or bottles through a Millex-GV 33 mm hydrophilic PVDFmembrane syringe filter (0.22 μm pore size). More than one filter wasused to filter the entire 500-mL solution, and the first few dropsthrough each filter were discarded.

Aliquots of the furosemide formulation (10 mL) were added to 12-mL glassvials (Fisherbrand Type 1 Class A Clear Borosilicate Glass SampleVials), and the vials were sealed with black phenolic caps withPTFE-faced white rubber liner. Then, the vials were stored in an oven at25° C., 40° C., and 60° C. for a specified duration of time (e.g., 1week). After storage for either 1 week, 2 weeks, 1 month, 2 months, 3months, or 6 months a vial was removed from the oven and the furosemideformulation was analyzed for visual appearance, pH, and to determine theamount of furosemide and/or impurities in the formulation. Analysis ofimpurities included determination of the amount of impurities2-chloro-4-furfurylamino-5-sulfamoylbenzoic acid and4-chloro-5-sulfamoylanthranilic acid, respectively designated as Peak Aand Peak B in the Tables below and HPLC chromatograms in FIG. 1.

Analysis by HPLC was conducted according to the methods described inTable 2, below, following dilutions of the formulations. Samples forHPLC analysis were diluted by a factor of 1,000 (serial dilutions by afactor of 100 and 10, to a concentration of ˜30 μg/mL furosemide) or afactor of 60 (to a concentration of ˜500 μg/mL furosemide), as specifiedin the description and tables below. The diluent was 1:1 methanol:pH 5.7buffer (prepared with 1,000 mL MQ water, 750 μL triethylamine, 250 μLformic acid, and adjusted to pH 5.7 with triethylamine).

Part II—Results

Results of the stability analysis are provided in Tables 3-24 below.Representative HPLC chromatograms for analyzed samples of selectedfurosemide formulations are depicted in FIG. 1 (analyte detectionanalysis was performed at 270 nm). All values determined by HPLC (i.e.,in Tables 3-6, 11-13, and 18-20) are the average of results from threeHPLC chromatograms obtained from a given sample.

Data in Tables 3, 11, and 18 for furosemide concentration as apercentage of theoretical (i.e., 30 mg/mL) were calculated based on astandard calibration curve and were obtained from HPLC samples that hadbeen diluted by a factor of 1,000. Data in Tables 4-6, 12, 13, 19, and20 for the area percentage of the furosemide peak, Peak A, or Peak B(versus the total area of all peaks integrated in the chromatogram) wereobtained from HPLC samples that had been diluted by either a factor of1,000 (for storage duration of 0 days, 1 week, 2 weeks, and 1 month) ora factor of 60 (for storage duration of 2, 3, or 6 months).

TABLE 1 Aqueous Furosemide Formulations Subjected to Stability StudiesFurosemide Captisol Tris Buffer Formulation (mg/mL) (mg/mL) (mg/mL) pH A30 100 25 7.4 B 30 200 25 7.4 C 30 300 25 7.4 D 30 200 25 8.4 E 30 100 07.4 F 30 200 0 7.4 G 30 300 0 7.4 H 30  200* 0 7.4 *Formulation H wasprepared with Captisol buffered with sodium phosphate.

TABLE 2 HPLC Methods for Analytical Analysis of Stored FurosemideFormulations HPLC Method for Storage Durations of 0 days, 1 week, 2weeks, 1 month, and 2 months Column Name Zorbax-RX C18, 5 μm, 4.6 mm ×150 mm information Catalog # 883967-902 Mobile Phase A pH 5.7 buffer(1,000 mL MQ water, 750 μL triethylamine, 250 μL formic acid, adjustedto pH 5.7 with triethylamine) Mobile Phase B Acetonitrile Flow rate 0.8mL/min Column temperature Ambient Autosampler Ambient temperatureInjection volume 5.0 μL Detector wavelength 270 nm Time % MobileGradient (minutes) Phase B 0.0 8 1.0 8 3.0 25 10.5 40 11.5 40 12.0 815.0 End HPLC Method for Storage Duration of 3 months Column NameZorbax-RX C18, 5 μm, 4.6 mm × 150 mm information Catalog # 883967-902Mobile Phase A pH 5.7 buffer (1,000 mL MQ water, 750 μL triethylamine,250 μL formic acid, adjusted to pH 5.7 with triethylamine) Mobile PhaseB Acetonitrile Flow rate 1.0 mL/min Column temperature AmbientAutosampler Ambient temperature Injection volume 5.0 μL Detectorwavelength 270 nm Time % Mobile Gradient (minutes) Phase B 0.0 5 2.0 54.0 25 10.5 40 11.5 40 12.0 5 16.5 End HPLC Method for Storage Durationof 6 months Column Name Zorbax-RX C18, 5 μm, 4.6 mm × 150 mm Catalog #883967-902 Mobile Phase A 10 mM KH₂PO₄ in Water (pH 4.77, unadjusted)Mobile Phase B Acetonitrile Flow rate 1.0 mL/min Column temperatureAmbient Autosampler Ambient temperature Injection volume 5.0 μL Detectorwavelength 270 nm Time % Mobile Gradient (minutes) Phase B 0.0 5 2.0 53.0 25 15 30 15.5 50 16.0 50 16.5 5 20 End

TABLE 3 Furosemide Concentration as a Percentage of Theoretical (30mg/mL) for Formulations Stored at 60° C. Formu- Duration of Storagelation 0 days 1 week 2 weeks 1 month 2 months 3 months A 101.28 98.0299.89 97.82 97.13 95.37 B 100.44 100.01 100.64 98.68 100.19 98.36 C100.45 98.90 101.74 101.14 99.67 97.07 D 101.55 99.74 98.92 104.38 99.94100.78 E 100.78 101.44 100.55 99.80 99.78 95.64 F 100.32 100.13 99.9299.04 100.22 99.10 G 103.43 102.63 101.12 101.45 101.92 102.06 H 101.15101.06 99.48 100.72 100.74 98.48

TABLE 4 Furosemide Area Percentage of Total Chromatogram forFormulations Stored at 60° C. Formu- Duration of Storage* lation 0 days1 week 2 weeks 1 month 2 months 3 months A 100 99.223** 100 99.37 98.1295.17 B 100 100 100 100 98.78 97.01 C 100 100 100 100 99.55 98.12 D 100100 100 100 99.48 98.32 E 100 100 100 100 98.84 96.08 F 100 100 100 10099.15 97.22 G 100 100 100 100 99.23 97.72 H 100 100 100 100 99.08 97.44*Samples for HPLC analysis were diluted by a factor of 1,000 (forstorage duration of 0 days, 1 week, 2 weeks, and 1 month) or a factor of60 (for storage duration of 2 months and 3 months). **Only one of threesamples analyzed contained peaks other than furosemide.

TABLE 5 Peak B Area Percentage of Total Chromatogram for FormulationsStored at 60° C. Formu- Duration of Storage* lation 0 days 1 week 2weeks 1 month 2 months 3 months A 0 0 0 0.63 1.12 3.051 B 0 0 0 0 0.681.913 C 0 0 0 0 0.27 1.237 D 0 0 0 0 0.33 1.138 E 0 0 0 0 0.72 2.473 F 00 0 0 0.52 1.735 G 0 0 0 0 0.45 1.423 H 0 0 0 0 0.59 1.615 *Samples forHPLC analysis were diluted by a factor of 1,000 (for storage duration of0 days, 1 week, 2 weeks, and 1 month) or a factor of 60 (for storageduration of 2 months and 3 months).

TABLE 6 Peak A Area Percentage of Total Chromatogram for FormulationsStored at 60° C. Formu- Duration of Storage* lation 0 days 1 week 2weeks 1 month 2 months 3 months A 0 1.09** 0 0 0.10 0.082 B 0 0 0 0 00.028 C 0 0 0 0 0 0.011 D 0 0 0 0 0 0.013 E 0 0 0 0 0 0.034 F 0 0 0 0 00.027 G 0 0 0 0 0 0.019 H 0 0 0 0 0 0.027 *Samples for HPLC analysiswere diluted by a factor of 1,000 (for storage duration of 0 days, 1week, 2 weeks, and 1 month) or a factor of 60 (for storage duration of 2months and 3 months). **Only one of three samples analyzed containedthis peak.

TABLE 7 pH for Formulations Stored at 60° C. Formu- Duration of Storagelation 0 days 1 week 2 weeks 1 month* 2 months 3 months A 7.492 7.4567.454 7.02 6.893 6.798 B 7.545 7.541 7.634 7.37 7.106 6.890 C 7.5367.533 7.531 7.46 7.335 7.112 D 8.426 8.414 8.427 8.31 8.387 8.213 E7.721 7.942 7.821 6.91 6.670 6.412 F 7.258 7.417 7.513 7.02 6.736 6.471G 7.499 7.380 7.361 6.93 6.623 6.394 H 7.568 7.450 7.407 7.13 6.7626.539 *A different pH meter was used to measure the samples stored for aduration of 1 month.

TABLE 8 Osmotic Pressure (in mOsm/kg) for Formulations Stored at 60° C.Duration of Storage Formu- Captisol 0 1 2 1 2 3 lation (mg/mL) days weekweeks month months months A 100 343 342 340 345 346 346 B 200 733 718759 717 720 734 C 300 1208 1285 1295 1307 1369 1435 D 200 724 762 749744 736 737 E 100 340 337 339 341 343 342 F 200 721 711 703 722 729 725G 300 1274 1226 1214 1192 1212 1232 H  200* 739 713 723 735 725 724*Formulation H was prepared with Captisol buffered with sodiumphosphate.

TABLE 9 Viscosity (in cP) for Formulations Stored at 60° C. Duration ofStorage Formu- Captisol 0 1 2 1 2 3 lation (mg/mL) days week weeks monthmonths months A 100 ND ND ND ND ND ND B 200 ND ND ND ND ND ND C 300 4.5- 5.09 5.0 4.7 4.90 4.50 4.2 D 200 ND ND ND ND ND ND E 100 ND ND ND ND NDND F 200 ND ND ND ND ND ND G 300 4.2 4.6 4.3 4.3 4.20 4.00 H  200* ND NDND ND ND ND *Formulation H was prepared with Captisol buffered withsodium phosphate. ** “ND” signifies that viscosity was not determinedfor the sample.

TABLE 10 Color of Formulations Stored at 60° C. Duration of StorageFormulation 0 days 1 week 2 weeks 1 month 2 months 3 months A ColorlessColorless Very Yellow Yellow Dark Yellow Slightly Yellow B ColorlessColorless Colorless Slightly Yellow Pale Yellow Pale Yellow C ColorlessColorless Colorless Very Slightly Yellow Slightly Yellow Slightly YellowD Colorless Colorless Colorless Very Slightly Yellow Slightly YellowSlightly Yellow E Colorless Colorless Colorless Yellow Yellow Yellow FColorless Colorless Colorless Slightly Yellow Pale Yellow Pale Yellow GColorless Colorless Colorless Slightly Yellow Pale Yellow Pale Yellow HColorless Colorless Colorless Slightly Yellow Pale Yellow Pale Yellow *All samples were clear solutions without visible precipitate.

TABLE 11 Furosemide Concentration as a Percentage of Theoretical (30mg/mL) for Formulations Stored at 40° C. Duration of Storage Formulation0 days 2 months 3 months 6 months A 101.28 100.33 97.69 98.03 B 100.44101.26 99.74 98.69 C 100.45 100.26 100.32 101.28 E 100.78 100.13 98.92101.39 F 100.32 100.82 99.97 100.95 G 103.43 103.76 103.69 103.87 H101.15 99.93 101.28 100.29

TABLE 12 Furosemide Area Percentage of Total Chromatogram forFormulations Stored at 40° C. Duration of Storage Formulation 0 days 2months 3 months 6 months A 100 99.64 99.26 98.43 B 100 99.93 99.75 99.49C 100 99.96 99.80 99.67 E 100 99.94 99.67 99.34 F 100 99.93 99.68 99.38G 100 99.93 99.65 99.18 H 100 99.94 99.67 99.29

TABLE 13 Peak B Area Percentage of Total Chromatogram for FormulationsStored at 40° C. Duration of Storage Formulation 0 days 2 months 3months 6 months A 0 0.16 0.478 0.94 B 0 0.07 0.151 0.351 C 0 0.04 0.1270.244 E 0 0.06 0.203 0.425 F 0 0.07 0.199 0.395 G 0 0.07 0.223 0.502 H 00.06 0.212 0.429

TABLE 14 pH for Formulations Stored at 40° C. Duration of StorageFormulation 0 days 2 months 3 months 6 months A 7.492 7.444 7.364 7.242B 7.545 7.523 7.485 7.494 C 7.536 7.500 7.494 7.528 E 7.721 7.930 7.7197.379 F 7.258 7.625 7.544 7.246 G 7.499 7.316 7.194 7.183 H 7.568 7.5317.403 7.200

TABLE 15 Osmotic Pressure (in mOsm/kg) for Formulations Stored at 40° C.Captisol Duration of Storage Formulation (mg/mL) 0 days 2 months 3months 6 months A 100 343 339 338 345 B 200 733 739 737 717 C 300 12081455 1316 1403 E 100 340 340 342 344 F 200 721 708 740 732 G 300 12741217 1244 1350 H  200* 739 750 742 746 *Formulation H was prepared withCaptisol buffered with sodium phosphate.

TABLE 16 Viscosity (in cP) for Formulations Stored at 40° C. CaptisolDuration of Storage Formulation (mg/mL) 0 days 2 months 3 months 6months A 100 ND ND ND ND B 200 ND ND ND ND C 300 4.5-4.2 5.1 4.6 4.7 E100 ND ND ND ND F 200 ND ND ND ND G 300 4.2 4.9 4.1 4.5 H  200* ND ND NDND *Formulation H was prepared with Captisol buffered with sodiumphosphate. ** “ND” signifies that viscosity was not determined for thesample.

TABLE 17 Color of Formulations Stored at 40° C. Duration of StorageFormulation 0 days 2 months 3 months 6 months A Colorless Very SlightlySlightly Slightly Yellow Yellow Yellow B Colorless Colorless ColorlessColorless C Colorless Colorless Colorless Colorless E ColorlessColorless Very Very Slightly Slightly Yellow Yellow F ColorlessColorless Colorless Colorless G Colorless Colorless Colorless ColorlessH Colorless Colorless Colorless Colorless * All samples were clearsolutions without visible precipitate.

TABLE 18 Furosemide Concentration as a Percentage of Theoretical (30mg/mL) for Formulations Stored at 25° C. Duration of Storage Formulation0 days 6 months A 101.28 98.23 B 100.44 98.88 C 100.45 99.18 E 100.7898.01 F 100.32 99.89 G 103.43 102.79 H 101.15 100.42

TABLE 19 Furosemide Area Percentage of Total Chromatogram forFormulations Stored at 25° C. Duration of Storage Formulation 0 days 6months A 100 99.75 B 100 99.88 C 100 99.86 E 100 99.85 F 100 99.82 G 10099.75 H 100 99.79

TABLE 20 Peak B Area Percentage of Total Chromatogram for FormulationsStored at 25° C. Duration of Storage Formulation 0 days 6 months A 00.162 B 0 0.082 C 0 0.079 E 0 0.101 F 0 0.124 G 0 0.148 H 0 0.137

TABLE 21 pH for Formulations Stored at 25° C. Duration of StorageFormulation 0 days 6 months A 7.492 7.500 B 7.545 7.608 C 7.536 7.595 E7.721 7.598 F 7.258 7.591 G 7.499 7.253 H 7.568 7.516

TABLE 22 Osmotic Pressure (in mOsm/kg) for Formulations Stored at 25° C.Captisol Duration of Storage Formulation (mg/mL) 0 days 6 months A 100343 349 B 200 733 717 C 300 1208 1270 E 100 340 342 F 200 721 735 G 3001274 1363 H  200* 739 726 *Formulation H was prepared with Captisolbuffered with sodium phosphate.

TABLE 23 Viscosity (in cP) for Formulations Stored at 25° C. CaptisolDuration of Storage Formulation (mg/mL) 0 days 6 months A 100 ND ND B200 ND ND C 300 4.5-4.2 5.3 E 100 ND ND F 200 ND ND G 300 4.2 4.2 H 200* ND ND *Formulation H was prepared with Captisol buffered withsodium phosphate. ** “ND” signifies that viscosity was not determinedfor the sample.

TABLE 24 Color of Formulations Stored at 25° C. Duration of StorageFormulation 0 days 6 months A Colorless Very Slightly Yellow B ColorlessColorless C Colorless Colorless E Colorless Colorless F ColorlessColorless G Colorless Colorless H Colorless Colorless * All samples wereclear solutions without visible precipitate.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1-12. (canceled)
 13. A pharmaceutical composition, consisting of: fromabout 40 mM to about 160 mM of a diuretic selected from the groupconsisting of 4-chloro-2-((furan-2-ylmethyl)amino)-5-sulfamoylbenzoicacid, a pharmaceutically acceptable salt thereof, and a mixture of theforegoing; from about 45 mM to about 190 mM of a sulfobutyl etherderivative of β-cyclodextrin; about 25 mM of a buffer comprisingtris(hydroxymethyl)aminomethane; optionally a pH adjusting agent; andwater; wherein the pharmaceutical composition has a pH value from about7.0 to about 8.5.
 14. (canceled)
 15. The pharmaceutical composition ofclaim 13, wherein there is from about 135 mM to about 145 mM of thesulfobutyl ether derivative of β-cyclodextrin in the pharmaceuticalcomposition.
 16. The pharmaceutical composition of claim 15, wherein thesulfobutyl ether derivative of β-cyclodextrin is sulfobutyl etherbeta-cyclodextrin sodium.
 17. The pharmaceutical composition of claim16, wherein there is from about 80 mM to about 100 mM of the diuretic inthe pharmaceutical composition.
 18. The pharmaceutical composition ofclaim 16, wherein there is about 91 mM of the diuretic in thepharmaceutical composition. 19-23. (canceled)
 24. The pharmaceuticalcomposition of claim 18, wherein the pharmaceutical composition has a pHof about 7.4.
 25. (canceled)
 26. The pharmaceutical composition of claim24, wherein less than 1% of the diuretic degrades upon storage of thepharmaceutical composition at 40° C. for 29 days.
 27. The pharmaceuticalcomposition of claim 24, wherein less than 1% of the diuretic degradesupon storage of the pharmaceutical composition at 25° C. for 24 months.28-43. (canceled)
 44. A pharmaceutical composition, comprising: about 30mg/mL furosemide, or a pharmaceutically acceptable salt thereof; about30% by weight of a sulfobutyl ether derivative of a β-cyclodextrin;about 25 mM of a buffer comprising tris(hydroxymethyl)aminomethane; andwater; wherein the pharmaceutical composition has a pH from about 7.0 toabout 8.5.
 45. The pharmaceutical composition of claim 44, wherein thesulfobutyl ether derivative of β-cyclodextrin is captisol.
 46. Thepharmaceutical composition of claim 45, wherein the pharmaceuticalcomposition has a pH from about 7.2 to about 7.6.
 47. The pharmaceuticalcomposition of claim 44, wherein there is 30 mg/mL furosemide, or apharmaceutically acceptable salt thereof pharmaceutical.
 48. Thepharmaceutical composition of claim 45, wherein there is 30 mg/mLfurosemide, or a pharmaceutically acceptable salt thereofpharmaceutical.
 49. The pharmaceutical composition of claim 46, whereinthere is 30 mg/mL furosemide, or a pharmaceutically acceptable saltthereof pharmaceutical.
 50. The pharmaceutical composition of claim 44,wherein there is 25 mM of said buffer.
 51. The pharmaceuticalcomposition of claim 45, wherein there is 25 mM of said buffer.
 52. Thepharmaceutical composition of claim 48, wherein there is 25 mM of saidbuffer.
 53. The pharmaceutical composition of claim 49, wherein there is25 mM of said buffer.
 54. A pharmaceutical composition, consisting of:about 30 mg/mL furosemide, or a pharmaceutically acceptable saltthereof; about 30% by weight of a sulfobutyl ether derivative of aβ-cyclodextrin; about 25 mM of a tris(hydroxymethyl)aminomethane buffer;optionally a pH adjusting agent; and water; wherein the pharmaceuticalcomposition has a pH from about 7.0 to about 8.5.
 55. The pharmaceuticalcomposition of claim 54, wherein the sulfobutyl ether derivative ofβ-cyclodextrin is captisol.